Abstract
The initiation of psychostimulant sensitization depends on the mesocorticolimbic dopamine (DA) system. Although many cellular adaptations has been reported to be associated with this addictive behavior, the overall influence of these adaptations on the network regulation of DA neurons has not been established. Here, we profile a network-driven slow oscillation (SO) in the firing activity of ventral tegmental area (VTA) putative DA and non-DA neurons and their correlation with locomotor sensitization induced by repeated administration of cocaine. One day after the last cocaine injection, the power of SO (Pso) significantly increased both in DA and non-DA neurons. Interestingly, the Pso in DA neurons was positively correlated, while Pso in non-DA neurons was negatively correlated with the level of locomotor sensitization. On the other hand, the firing rates of DA and non-DA neurons were both elevated, but none exhibited any correlation with the level of sensitization. Fourteen days after the last injection, the Pso of DA neurons dissipated but still positively correlated with the level of sensitization. In contrast, the Pso in non-DA neurons lost correlation with locomotor sensitization. These results suggest that cocaine-induced locomotor sensitization is associated with long-term network adaptation in DA system and that DA and non-DA neurons may corporately facilitate/hamper the initiation of locomotor sensitization.
Highlights
The mesocorticolimbic dopamine (DA) circuit, as the center for drug abuse and addiction[1,2], undergoes long-term adaptations in response to repeated drug use, which promotes a risk of relapse after drug withdrawal[3]
The treatment regimen used in the present study produced behavioral sensitization in 64% of the cocaine-treated animals, yet only 18% of saline-treated rats met the criterion for behavioral sensitization (Fig. 1A–C)[31]
We report here that repeated cocaine injections selectively enhance power of SO (Pso) in the firing sequences of ventral tegmental area (VTA) DA and non-DA neurons after 1 day of withdrawal, which may contribute to sensitized and non-sensitized conditions
Summary
The mesocorticolimbic dopamine (DA) circuit, as the center for drug abuse and addiction[1,2], undergoes long-term adaptations in response to repeated drug use, which promotes a risk of relapse after drug withdrawal[3]. Several studies in brain slices have demonstrated that exposure to psychostimulants elicits drug-evoked synaptic plasticity in both excitatory and inhibitory inputs in VTA DA and non-DA neurons[3,9,10,11,12] Another important mechanism that the altered activity is through intrinsic regulation of ion channels such as GABAB receptor (GABABR)-dependent G-protein-gated inwardly-rectifying K (GirK) channel[13,14]. Repeated cocaine administration results in an initial increase and later decrease over withdrawal time in the number of spontaneously active VTA DA neurons and in their mean firing rate[18,19] It facilitates the switch of DA neuron firing from single-spike to burst, which augments DA release in the VTA and nucleus accumbens[20,21]. We extract the SO from the firing sequences of these neurons and find a strong correlation between the power of SO and the level of behavioral sensitization
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